The ability to initiate movement is essential for performing activities of daily living. Beginning at retirement age, bradykinesia, a significant decrease in locomotor activity, poses a major risk of impairment to this ability, disabling 15% of those reaching age 65 and 50% of those reaching age 85. The impending explosion in the retirement-aged population and their projected increase in longevity make it now imperative to determine the neurobiological basis of age-related bradykinesia and lifestyle strategies that can be initiated at middle-age to reduce its risk. Bradykinesia is a cardinal symptom of Parkinson's disease (PD) that appears when striatal dopamine (DA) loss exceeds 70%. Age-related bradykinesia is very much unlike PD in this regard, as striatal DA loss varies considerably but never exceeds 70%. However in the substantia nigra (SN), PD and aging decrease DA loss to a similar extent. Nigral dopamine release is well established, but the fact that nigral DA can affect behavior has been rather neglected. Indeed, interference with nigral DA signaling impedes locomotor activity. We have recently reported a significant correlation of nigral, but not striatal DA with locomotor activity. Nigral DA could therefore be targeted to improve age-related bradykinesia. Tyrosine hydroxylase (TH) is the rate-limiting enzyme in DA biosynthesis, is regulated by phosphorylation, and is influenced by the growth factor GDNF. Notably, GDNF increases locomotor activity, nigral DA tissue content, and nigral TH phosphorylation at ser31. This phosphorylation site has significant influence on DA tissue content. Aging decreases the expression of the GDNF receptor GFR ?-1, TH protein, ser31 TH phosphorylation, and DA in the SN. We propose these deficits contribute to age-related bradykinesia. Strategies shown to mitigate bradykinesia, exercise and caloric restriction (both of which also increase GDNF expression), are proposed to prevent these aging-related molecular deficiencies in SN. We will determine if age-related decreases in nigral DA contribute to age-related bradykinesia by 1) experimentally inhibiting TH activity in young rats to decrease DA and quantifying its impact on locomotor activity, and 2) bypassing deficient TH activity in aged rats with nigral L-DOPA infusion to quantify the impact on bradykinesia. We will also determine if the interventions of exercise or caloric restriction between 12 and 18 months of age (the period when nigral TH and DA decrease) will increase nigral levels of GFR ?-1, TH protein and ser31 TH phosphorylation, and DA. This collaborative project will identify therapeutic strategies to improve locomotion in the elderly and determine the molecular impact of lifestyle strategies shown to alleviate bradykinesia when initiated during middle-age. PUBLIC HEALTH RELEVANCE: The elderly face a significant risk of impaired mobility, especially bradykinesia. With the burgeoning increase in the elderly population in the United States, it is now critical to identify the neurobiological basis of age-related bradykinesia. Doing so will accomplish two things; 1) allow our older citizens to maintain the quality of life necessar for successful daily living, and, 2) determine what lifestyle strategies the middle-aged American can do to prevent age-related bradykinesia with advancing age. At this time, aging-related bradykinesia is not treatable. Our proposal will examine mechanisms by which dopamine and its regulating-enzyme, tyrosine hydroxylase, are affected by aging and what interventions, namely exercise and caloric restriction, may be beneficial to curtail age-related deficits. The benefit of these studies will make it possible to develop pharmacological and environmental therapeutic strategies to improve locomotion in the elderly and identify the molecular impact of lifestyle strategies that prevent bradykinesia.